Practice Essentials

Systemic sclerosis (also scleroderma) is a chronic, autoimmune rheumatic disease affecting the skin and other organs. The hallmark of the disease is thickening/tightening of the skin and inflammation/scarring of various organs/body parts, leading to involvement of the lungs, kidneys, heart, intestinal system, and other areas. There is no cure for scleroderma but effective treatments for some features of the disease are available. The disease is relatively uncommon. About 75,000–100,000 people in the United States have the disease; most are women between the ages of 30 and 50 years. Twins and family members of those with scleroderma or other autoimmune connective tissue diseases, such as lupus, may have a slightly higher risk of developing scleroderma. Children can also get scleroderma, but the disease is different in children from that in adults. Although the underlying cause is unknown, research is shedding more light on the relationship between genes, the immune system and scleroderma. Research is also underway to find better treatments for scleroderma and, hopefully, one day a cure.

There are two main categories of scleroderma:

Localized scleroderma affects skin, underlying connective tissues to a greater or lesser extent. Discolored, thickened patches of skin, termed morphea, may be so subtle as to escape the examiner's attention unless pointed out. When streaks/bands of thickened tissue involve a limb, it is termed linear scleroderma. Linear scleroderma involving the face, forehead, and scalp is termed “scleroderma en coup de sabre.” Diffuse cutaneous scleroderma without systemic involvement can occurr, but rarely.

Systemic scleroderma (systemic sclerosis), which is the most serious form of the disease, affects skin, muscles, bones, joints, blood vessels, lungs, kidneys, heart, and virtually all organs. Progressive systemic sclerosis is a rare, inexorably progressive disease that leads to an early death.

There is no known cause. Genetic factors and the immune system appear to be important in disease development and progression. Although exposure to certain chemicals and drugs may play a role in some children developing scleroderma, the vast majority of patients do not have a history of exposure to any suspicious toxins. It should be noted that as with other rheumatic diseases of childhood, cases with features of two or more conditions is not uncommon. Most overlap cases have features of scleroderma and dermatomyositis. In some children it may take years before a definitive diagnosis is possible.

Next:

Background

Juvenile systemic sclerosis (JSSc) is a rare connective tissue disease of unknown etiology. Characteristic features include fibrosis of the skin, subcutaneous tissues, and internal organs as well as abnormalities of the vascular and immune systems occurring in children 16 and younger. This disease is one of the most severe rheumatologic conditions diagnosed in children.

Previous

Next:

Pathophysiology

One of the earliest processes thought to occur in JSSc is vascular injury. This results in upregulation of endothelial cell adhesion molecules, which facilitates local platelet aggregation and infiltration of inflammatory cells. This endothelial injury is manifested clinically as Raynaud phenomenon, pulmonary hypertension, and renovascular hypertension.

These inflammatory cells release cytokines, including transforming growth factor beta (TGF-β) and interleukin-1 (IL-1). Among its many effects, IL-1 is known to stimulate the release of platelet-derived growth factor, which stimulates fibroblasts to increase production and deposition of extracellular matrix components such as collagen, fibronectin, and glycosaminoglycans. This fibrosis may affect any organ of the body, most commonly the skin, GI tract, lungs, heart, kidneys, and musculoskeletal system.

Little is known about the role of the various autoantibodies, such as ANA, seen in almost all cases of juvenile systemic sclerosis, but their presence is suggestive of an autoimmune process underlying the aforementioned vascular injury and fibrosis. Resistance of lymphocytes to apoptosis seen in these patients is a potential mechanism for the persistence of autoreactive T cells in JSSc.

Previous

Next:

Epidemiology

Frequency

United States

JSSc is a rare childhood disorder, an orphan disease whose incidence is said to be approximately 0.05 per 100,000 children.
[1] In addition, 5-10% of adult cases of systemic sclerosis arise before age 16 years, thus meeting the age criterion for JSSc. New criteria aimed at more uniformly defining JSSc will hopefully aid in better estimation of incidence and prevalence of the condition.

Mortality/Morbidity

Mortality rates in JSSc are reportedly lower than in adult systemic sclerosis. Five and 20-year survival rates for JSSc are 89% and 69%, respectively. This is likely a reflection of the increased incidence of simple morphea in children.

The greatest morbidity and mortality is seen in those children who develop pulmonary, cardiac, and renal manifestations of the disease. A recently published report reveals that the most significant predictors of mortality at the time of diagnosis are pericarditis, elevated creatinine levels, and fibrosis on chest radiography.
[2] The most common cause of early death in patients with juvenile systemic sclerosis is heart failure due to dilated cardiomyopathy, likely related to pulmonary hypertension and myocardial fibrosis.

In a review of 153 patients, those who died had a significantly shorter time to diagnosis from onset of symptoms compared with patients that were still alive at follow-up 8.8 vs 23 months.
[3] This demonstrates that those patients who eventually die due to complications of JSSc likely have a more aggressive form that is more quickly recognized due to the severity of symptoms. This is consistent with mortality rates of most studies that show most deaths from JSSc occur within the first 5 years after diagnosis.

Morbidity from the disease is seen in most patients in the form of fibrosis of the skin, which may lead to contractures and loss of mobility, and Raynaud phenomenon with associated pain and paresthesias, as well as digital ulcers. Arthralgias, arthritis, and muscle weakness may occur in as many as a quarter of patients, and a small number may experience dyspnea, weight loss and dysphagia as well.

Race

In the United States, adult systemic sclerosis is more common in blacks than in whites, with a ratio of 2:1. No specific demographic data are available for JSSc, however in the senior author's experience children of color (African-American, Hispanic, Asian, and Pacific Islanders) made up the majority of patients followed in our clinics.

Sex

Females are affected more often than males, with an overall female-to-male ratio of approximately 3.6:1, much lower than the 15:1 female-to-male predominance seen in adults.

Age

By definition, the child must be younger than 17 years at the time of disease onset to the meet the criteria for JSSc. The youngest patient documented with JSSc was only a few months old at disease onset. The average age of onset is 8.1–8.8 years in the two largest published case series. Due to the rarity of this condition and the subtle nature by which it can first appear, the average time from symptom onset to diagnosis is 1.9 years, taking as long as 12 years in some cases. Of note, children who died in these studies were diagnosed almost 2 years later than the average child with juvenile systemic sclerosis.

Previous

Next:

Prognosis

Prognosis is dependent on the extent of the disease. Children with limited forms of the disease (eg, morphea) have an excellent prognosis both for function and life. The survival of JSSc at 5 years, 10 years, 15 years, and 20 years after diagnosis is 89%, 80–87.4%, 74–87.4%, and 69–82.5%, respectively. These survival rates are significantly higher than those reported in patients with adult-onset systemic sclerosis.

If linear scleroderma involves the child's dominant hand there may be significant writing restriction and note-taking in the classroom may be compromized. Arrested leg growth, seen in linear scleroderma may result in significant gait disturbances and orthotics in the form of lifts or inserts may be required. Severe scleroderma en coup de sabre involvement of the child's face has led to severe depression, sometimes with sucidal ideation. Fortunately rare, progressive systemic sclerosis is a slowly developing, progressive condition, which, when it involves the esophagus, lungs, kidney, etc. leads inexoriably to death.

The most common causes of death are secondary to complications of cardiac, renal, or pulmonary involvement and failure. A study by Martini et al studied 134 patients with JSSc.
[4] All patients who died had a diffuse form of the disease, with rapid progression and early signs of internal organ involvement, suggesting two courses: a more rapid course and a slow course with lower mortality.

Regular and frequent monitoring of cardiac, renal, and pulmonary function are critical while caring for this patient population. However, further research is still required to better define disease activity so that a standardized approach to treatment of this disease may be established.

Previous

Next:

Patient Education

There is almost no information available concerning patient education in JSSc. If the rheumatologist is fortunate enough to have a multidisciplinary team available including a nurse, social worker, physical therapist, occupational therapist, and nutritionist then the development of a self-help group may be possible. A small pilot study involving adult women in Sweden suggests that this approach appears to be useful. Skin care and pain were common concerns of the patients in that study.
[5]